Peptides having binding affinity to an antibody which recognizes an epitope on an alpha1 loop 2 or beta2 loop 1 of an adrenoreceptor

ABSTRACT

A peptide having an ED 50  of less than 500 nm, in particular 10 nM to an antibody which recognizes an epitope on an extracellular α1 loop 2 or β2 loop1 of a human adrenoceptor wherein the antibody&#39;s binding to the epitope results in an increase of γ-secretase activity, an increased release of β-amyolid molecules and/or cellular dysfunction of cerebral blood vessel cells, glia cells or neurons, wherein the ED 50  value is measured by bioassay.

The invention pertains to a peptide having a binding affinity anantibody which recognizes an epitope on an α1 loop 2 or β2 loop1 of anadrenoreceptor, an isolated nucleic acid molecule, solid phases foraffinity chromatography or solid-phase extraction consisting of organic,inorganic, synthetic polymers or of mixed polymers, a vector comprisinga nucleic acid molecule, a host cell comprising the vector, a device forremoving immunoglobulins from immunoglobulin-containing fluids on solidphases, a pharmaceutical composition comprising a nucleic acid molecule,a peptide and/or a solid phase of the invention together with apharmaceutically tolerable carrier, a kit comprising a nucleic acidmolecule of the invention, a vector of the invention, a host cell of theinvention, as well as an apparatus for chromatography, comprisingpeptides of the invention.

Alzheimer's disease (AD), which is named after its discoverer AloisAlzheimer (1864-1915), is a progressive degenerative disease. It ischaracterized by changes in the cerebral cellular structure and functioncaused by deposits of aggregated proteins with extensive consequencesfor essential brain functions. The following clinical and cognitivecharacteristics are essential:

-   -   disorders of the short-term memory at first and of the long-term        memory later on    -   disorders of the perception of simple recognition patterns    -   progressive loss of speech and articulateness    -   progressive loss of sense of smell, of spatial orientation and        decline of ability to perform routine tasks.

The diagnosis “AD” is obtained by different methods, for example, withimaging methods, such as computer tomography (CT) or magnetic resonancetomography (MRT) and by the chemical determination in the laboratory ofthe concentrations of the involved pathological molecules in thecerebrospinal fluid. Electroencephalography (EEG) may also be recurredto. Cognitive tests, such as the mini mental status test (MMST) areincreasingly gaining importance.

If untreated, the disease is a “one-way street” which unavoidablyresults in a deterioration of the clinical image over several years toend with death. The more advanced the stage of the disease, the morecare and cost intensive the patient becomes. This also holds for otherforms of dementia (AD accounting for about two thirds of all dementiacases), which will not be dealt with here, however.

The prevalence of the disease is highly age-dependent. Among those of 60to 70 years of age, it is about 1%, and among those of 70 to 80 years ofage, it is as high as about 10%. Since life expectancy of the humans inGermany is continuously increasing, another rise of the number of casesis to be expected.

Currently, the annual incidence for AD in Germany is 130 000 to 140 000incidences (Hallauer, 2003), a number that needs interpretation,however. Since the mild form is little conspicuous, the majority of thepatients will probably have a medium severity of the disease.

Some years ago, the disease was still considered a stroke of fate thatcould not be cured. Severe cases have been treated with sedatives andneuroleptics for sedation. In the meantime, drugs of the firstgeneration are available; they are mainly employed in the medium,moderate stage. Examples include approved pharmaceuticals, such as Axura(active ingredient: memantine) or Exelone (active ingredient:rivastagmine). According to the published state of the study, theseagents have a good effectiveness for mild and medium severities of AD.

However, the clinical effectiveness of Exelone and othercholine-esterase inhibitors is denied according to metaanalyses.Although approved medicaments are available on the market and thepreparations are prescribable, by far not all patients are treated.

Some prophylactic effect on AD seems to be exerted by anti-inflammatorydrugs, such as acetylsalicylic acid (aspirin), ibuprofen, indomethazineor COX2 inhibitors. Evidently, local and systemic inflammations orinflammation mediators play a disease-promoting role in theorganism/brain, probably due to an acceleration of neurofibrilformation.

Cholesterol-reducing agents, such as statins, also seem to have afavorable influence on the risk of developing AD. At least, patientsobtaining cholesterol-reducing agents exhibit a lesser incidence of AD.However, no hard scientific data are available to support this.

The situation is similar with hypotensive agents, such as inhibitors ofangiotensin converting enzyme (ACE). In addition to a direct effect ofthese active substances, the reduction of the systolic blood pressure isalso generally associated with the preventive effects observed.

Immunizations of patients with β-amyloid are in the experimental stageof a therapy. In response, the immune system produces antibodies whichthen destroy amyloid plaques by a local inflammatory reaction. Thisapproach seems to be promising, but is not undisputed, because itinvolves high risks. Probably, the individual inflammatory immuneresponses that are used therapeutically cannot be dosed as precisely aswould be required. Other experimental-therapeutic approaches are basedon the compensation of a cerebral deficiency of copper ions, whichevidently plays a role in plaque formation.

The question of whether medicaments are basically able to achieve astandstill only, or also a clinical improvement of the patients'cognitive state is currently still unanswered. The currently availablemeans stabilize the clinical picture rather than improve it.

The pathogenesis of AD itself has not yet been finally clarified. Anumber of risk factors have been recognized. These include age,hypertension, high cholesterol levels, overweight, apolipoprotein E4,copper deficiency, certain genetic predispositions, and possiblyoxidative stress. The development of the disease is very probablymultifactorial.

There is a plethora of references about molecules that play or couldplay a role in the development and progress of AD. As to a definition ofterm, it may be mentioned here that most of the so-called pathologicalmolecules are components of physiological structures and processes inthe healthy organism. They are considered pathological if they exceedconcentration limits, in the plasma or locally in the tissue,intercellular or intracellular. This holds for both dissolved proteinsand aggregated molecules (e.g., β-amyloid in the form of plaque).

The aggregation or deposit of two different, per se physiologicalprotein molecules in the brain in intercellular or intracellular spacescauses fundamental neuronal functional disorders in signal transmissionand the interaction of neurons. These proteins are essentially theneurotoxic β-amyloid peptide (aggregated as a polymer in the form ofamyloid plaque), and the Tau protein, a polymer aggregated asneurofibrillary tangles.

So-called amyloids are evidently involved causally in the development ofAD. Thereafter, an increased formation of amyloid-β40/42 occurs byenzymatic cleavage of the molecule from the membrane of the nerve cells.This results in a locally increased concentration of single β-amyloidmolecules, β-amyloid oligomers and its aggregation into amyloid plaques.These plaques disrupt the normal transmission of stimuli by the nervesand communication between the cells. The cleavage of aggregatableβ-amyloids from the precursor molecules is effected by the so-calledγ-secretase. The activity of this enzyme is controlled by theβ2-adrenoceptor.

The plaques in turn may also result in the generation of neurofibrillarytangles of the Tau protein, which normally is physiologically localizedin the axonal tracts of the nerve cells. The deposit of these aggregatestakes place in a wide variety of cerebral areas. The process of plaqueformation proceeds over many years from the beginning to the onset ofthe disease.

Both plaques and neurofibrillary tangles can be visualized well bymicroscopy in brain sections of dead AD patients and are an importantpart of diagnostics.

A pathomechanistic role of other molecules is also discussed inparallel, including the role of apolipoprotein E4. Further,rheologically relevant plasma proteins seem to be involved in thedevelopment of the clinical picture at least indirectly. These includeincreased or moderately increased systemic levels and localconcentrations of alpha-2 macroglobulin, fibrinogen, but also oxidizedplasma proteins from oxidative stress reactions, such as oxidized lowdensity lipoprotein (oxLDL).

The sum of effects of these molecules may contribute to a reduced bloodcirculation through the brain areas and thus induce the beginnings ofthe disease and promote its development and maintenance. Table 1provides a survey of important pathological molecules.

TABLE 1 Survey of pathological molecules of Alzheimer's disease in theblood plasma Pathological molecules in AD MW Comment fragments of <4,000fragments of β-amyloid having β-amyloid neurotoxic properties oligomersof >4,000 β-amyloid β-amyloid or >70,000 albumin is the most importantfragments thereof plasma protein for the bound to albumin physiologicalclearance of noxious substances apolipoprotein E, ca. 34,000 predisposedfor AD, may be especially E4 (monomer) contained in plaquesproinflammatory 16,000-50,000 increased levels in brain, cytokines IL1β,IL6, (monomer and neurotoxic TNFα trimer, respectively C-reactiveprotein 120,000 involved in plaque formation, (CRP) enhances celldegradation in necroses fibrinogen 340,000 rheologically effective dueto its size, reduces circulation through capillaries L-kynurenine 208neurotoxic precursor of 3OH—K, interacts with glutamate receptorshomocysteine, 268 inhibits the degradation of unbound ADMA and thusreduces vasodilatation asymmetric 202 inhibits NO synthetase anddimethylarginine thus results in hypoperfusion (ADMA) oxidative stressvariable, also can be induced directly by β- (reaction products)microparticles amyloid, but are also formed by hypoperfusion

The most extensively studied group of diseases associated with agAABagainst GPCR are cardiac diseases. In myocarditis, dilatedcardiomyopathy, peripartum cardiomyopathy, Chagas' disease, andventricular arrhythmias, agAAB against the β₁-AR can be detected in thesera of patients with clinically diagnosed diseases.

DCM and myocarditis are severe heart disorders, and it has beenhypothesized that a chronic myocarditis may develop to a DCM. In bothdiseases an infection with an enterovirus or others may be the primaryetiological agent, but the inflammatory response may have developed toan autoimmune disease. In a later stage, the infectious agent may not bedetectable, and even the inflammatory response may have declined,however, a chronic progressing heart failure is diagnosed. The DCM ischaracterized by a severe heart failure. In a subset of DCM, theidiopathic DCM, in which other etiological agents can be excluded, theprevalence of the β₁-adrenergic AAB of up to 80% is remarkable.

Myocarditis and DCM are preferentially treated by antagonists of theβ1-adrenergic and renin-angiotensin system and physical rest.

The therapeutic goal is to reduce cardiac overstimulation and preventarrhythmias The therapeutic use of betablockers in reducing adrenergicoverstimulation is accompanied by a significant decrease in cardiacdeath and hospitalization in the patients subject to the study.Ventricular arrhythmias are a major cause of sudden death in dilated DCMand ventricular tachycardias have been shown to be strongly related withthe detection of agAAB to the β₁-AR.

The chronic progression of heart failure in DCM leads to a stage of thedisease where successful medication is not possible anymore. In thisstage, only heart transplantation can be considered as a therapysustainable for some year. DCM is the cause of about half of the hearttransplantations. An extension of therapeutic options might very likelyprevent a substantial number of premature deaths in the case of severeheart failure.

Similar to DCM, peripartum cardiomyopathy is characterised by a dilationof the left ventricle and may develop into a life threatening disorder.The incidence is about 1:1000 in South African women, while the diseaseis rare among white populations in western countries. The etiology ofperipartum cardiomyopathy is largely unknown. By definition it isdiagnosed between the last month before and the 4^(th) month afterdelivery. Recently, the presence of agAAB against the β₁-AR in all seraof a sample of 10 patients suffering from peripartum cardiomyopathy wasshown.

Chagas' disease is caused by the parasite Trypanosoma cruzi and verycommon in South America. Among other symptoms, the patients oftendevelop a myocarditis as part of the dysautonomic syndrome that affectsthe whole cholinergic system. There is strong evidence that thedysautonomic syndrome is caused also by functional AAB against themuscarinic M₂-acetylcholine receptor. The prevalence of agAAB againstthe M₂-receptor ranges from 50-94%. In Chagas' disease, AAB against theβ₁-AR can also be found in about 53% of the cases. This situation mayrepresent the antigenic mimicry of originally the same antigen from T.cruzi, with a functional antagonism as an epiphenomenon.

With respect to the pathogenetic nature of the described agAAB, only thesignalling events with evidence of clinical relevance will be consideredin the following paragraph. Activation of the β-AR leads to an elevationof cAMP by the activation of adenylate cyclase by stimulatingG_(s□)-proteins in the G-protein trimer. On the other hand, agonisticligand binding to muscarinic and nicotinic acetylcholine receptorsinhibits adenylate cyclase by inhibiting G_(i□)-proteins. However, thissimple pattern has to be extended for the individual receptors.

Autoantibodies from sera of myocarditis or DCM patients show a positivechronotropic effect to the same extent as the agonist isoprenaline.Isoprenaline clearly increases the cAMP concentration in the cell andactivates the L-type Ca²⁺-channels. It has been shown that AAB from DCMpatients activate the L-type Ca²⁺-channels. On the other hand, theeffect of AAB on the accumulation of cAMP was rather marginal. It hasbeen shown, however, that the cytosolic as well as the membrane boundprotein kinase A in cardiomyocytes is activated upon AAB-stimulation. Amonoclonal anti-B₁-receptor AB that induces apoptosis in ratcardiomyocytes also acts via cAMP and protein kinase A, MAP-kinases,esp. p38-kinase are activated downstream of several GPCRs but also inthe signal transduction cascade of inflammatory cytokines. Thus, it maybe suggested that stimulation of the β₁-AR by agAAB may also have aproinflammatory effect.

There are also important cAMP-independent signalling pathways. L-typeCa²⁺-channels are not only activated through phosphorylation by proteinkinase A, but also directly through subunits of G-proteins. Thus, thestimulation of Ca²⁺-influx may be a significant pathway for thepathogenetic role of AAB in autoimmune myocarditis and DCM. The actionpotential on rat and human cardiomyocytes is prolonged by theadministration of agAAB against the β₁-AR and activates in turn theelectrogenic Na⁺/Ca²⁺-exchanger, resulting in electrical instability ofthe heart. Intracellular calcium overload is also known as a key eventof remodelling, as is the β₁-adrenergic stimulation. In a transgenic ratmodel, the β₁-AR was crucial for the reorganization of actin mediated byenhanced transcription of the atrial natriuretic factor.

Taken altogether, β-adrenergic overstimulation, intracellular calciumoverload, and the partial lack of down regulation of the β₁-AR may beinvolved in the pathogenesis of myocarditis and DCM.

Results from animal experiments support the in vitro data about thepathogenic relevance of agAAB obtained in tissue culture experiments.Jahns et a. could induce agonistic antibodies in rats by immunisationwith the second extracellular loop of the β1-AR. The animals developed adilated cardiomyopathy similar to that of human dilated cardiomyopathy.The transfer of the induced antibody/immunoglobobulins into healthyanimals leads to a DCM also.

The induction of agonistic antibody against the β1-AR was also performedin rabbits and results in the occurrence of agAAB as well as DCM. Aremoval of agAAB from the animal's blood plasma by specificimmunoadsorption using a peptid column leads to an improvement of theheart muscle function, measured as left ventricular ejection fraction.

More as a dozen publications report about the clinical benefit of thetheapeutical apheresis (immunoadsorption) in patients suffering fromDCM. In a clinical stage of the cardiac disease where no successfulcardiac drug medication is possible, the therapeutical apheresis leadsto a long lasting decline of the agAAB, a disappearance of activatedinflammatory leukocytes from the heart muscle tissue and an increase ofessential cardiac functions.

Other examples of diseases which are associated or caused by agAABpreeclampsia and vascular necrotic kidney rejection (agAAB against theAngiotensin-1 receptor or the open angle glaucoma (agAAB against theβ2-adrenoceptor.

WO-A-02/093174 discloses a method and device for treating AD. The methodinvolves the removal of circulating autoantibodies of a biochemicalmarker of markers, specifically human glial fibrillary acidic protein(GFAP) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in bodyfluid, preferably blood or a blood product. The invention furtherincludes a device or process of immune system modulation effective forautoantibody removal.

D. M. Walsh et al. discloses in Biochemical Society Transactions (2005)Vol. 33, part 5, PP 1087-1090 that soluble oligomers of Aβ are among theearliest effectors of Alzheimer's disease. They report about testing ofcompounds directed at three prominent amyloid-based therapeutic targets,inhibition of the secretases responsible for AR production, inhibitionof Aβ aggregation and immunization against Aβ. In each case, compoundscapable of reducing oligomer production or antibodies that avidly bindAβ oligomers also ameliorate the synaptotoxic effects of these natural,cell-derived oligomers. Norman R. Relkin et al. discloses inNeurobiology of Aging (2008), February 20, E-publ. that naturaloccurring antibodies against βA are able to reduce the βA level in thebody, and their intravenious application may improve the brain functionin patients with mild AD.

Dennis 3. Selkoe et al. Report in Annu. Rev. Pharmacol. Toxicol. 2003,43:545-84 discusses molecular understanding predicting amyloid-basedtherapeutics. Degenerative diseases of the brain were long consideredamong the most obscure and intractable of human maladies. However,recent advances in understanding their mechanisms have brought us to theverge of potential disease-modyfying agents. This progress is perhapsbest exemplified by the case of Alzheimer's disease. The application ofmolecular pathology and genetics has led to the recognition that thefour genes implicated to date in familial Alzheimer's disease allchronically elevate cerebral levels of the Amyloid β-protein (Aβ).Accordingly, small molecule inhibitors of the β- and γ-secretases, theproteases that generate Aβ from its precursor, are under acticedevelopment, and some have shown in vivo efficacy in mouse models. Analternative approach, active or passive immunization against Aβ, hasreceived extensive pre-clinical validation in mice, but an effectivepreparation free of significant side effects in humans is still awaited.Several other potential therapies are also reviewed here. If one or moreof these varied approaches is ultimately proven to slow or preventdementia, Alzheimer's disease will become a salient example of thesuccessful application of reductionist biology to the most complex oforgans, the human cerebral cortex.

EP-A-1832600 discloses an invention which relates to nucleic acidmolecules encoding peptides which interact with autoantibodiesassociated with glaucoma, to the peptides themselves, to apharmaceutical composition comprising said nucleic acid molecules andpeptides, and to the use of said peptides—especially in apheresis—forthe treatment of glaucoma. The peptides represent an epitope which is apart of the extrcallular loop2 of the β2 adrenergic receptor.

WO-A-02/38592 discloses an invention which relates to peptides having ahigh affinity to immunoglobulins.

Y. Magnusson et al. report in Clin. Exp. Immunol. (1989) 78, 42-48 aboutan antigenic analysis of the second extra-cellular loop of the humanbeta-1 adrenergic receptor which is different to the beta-2 adrendergicreceptor.

Yanxiang Ni et al. report about activation of β₂-adrenergic receptorstimulating γ-secretase activity and accelerating amyloid plaqueformation. They report that β₂-AR activation can stimulate γ-secretaseactivity and amyloid plaque formation and speculates that abnormalactivation of β₂-AR might contribute to Aβ accumulation in Alzheimer'sdisease pathogenesis.

An object of the invention was to provide a compound which is able to beused in the treatment of AD. Another object was to provide a compoundwhich is able to reduce the 32-adrenoceptor mediated γ-secretaseactivity in individuals suffering from higher levels of γ-secretase dueto auto-antibodies against adrenoreceptor.

The invention is based on the finding of agonistic autoantibodies(agAAB) directed against the G protein coupled receptors (GPCR), β2 andα1 adrenoceptor (AR), in the blood plasma of patients suffering fromdiseases caused by an increase of γ-secretase activity, an increasedrelease of β-amyolid molecules and/or cellular dysfunction of cerebralblood vessel cells, glia cells or neurons. In particular, the disease isAD.

In one embodiment of the present invention the object is solved byremoving immunoglobulins from patients being suspect of suffering fromor suffering from a disease caused by an increase of γ-secretaseactivity, an increased release of β-amyolid molecules and/or cellulardysfunction of cerebral blood vessel cells, glia cells or neurons. Theremoval of immunoglobulins may be performed by adsorption of therespective immunoglobulins on a solid support. These methods as such arewell known in the art.

In a further embodiment the invention is concerned with the use of animmunoadsorption device for manufacturing a device for the treatment ofa disease caused by an increase of γ-secretase activity, an increasedrelease of β-amyolid molecules and/or cellular dysfunction of cerebralblood vessel cells, glia cells or neurons by removal of immunoglobulinsfrom patients.

In another embodiment of the invention the object is solved by a peptidehaving an ED₅₀ of less than 500 nM, in particular 10 nM to an antibodywhich recognizes an epitope on a human α1 loop 2 and β2 loop1 of anadrenoreceptor wherein the antibody's binding to the epitope results inincrease of γ-secretase activity and/or increased pathological β-amyloidrelease and/or cellular dysfunction of cerebral blood vessel cells, gliacells or neurons, wherein the ED₅₀ value is measured by the bioassaywhich was used to identify the agAAB.

In particular, the peptide of the invention recognizes the human α1 loopepitopes of α-adrenoreceptor subtypes A, B, or C or combinationsthereof.

In one embodiment of the invention the peptide of the invention consistsof an amino acid sequence

X1-X2-X3-X4-X5-X6-X7-X8-X9

-   -   wherein    -   a)    -   X1=amino group, amide, acetyl group, biotin group, marker,        spacer, linker, C, GKK, SGKK (SEQ ID NO:6) or deletion,    -   X2=A, G, α-Abu, F, Hph, Hyp, Nal, P, Pip, S, V, W, Y, or        deletion,    -   X3=Hyp, P, Pip, S, T, Y, or deletion,    -   X4=Aad, Asu, D, E, Har, K, N, Orn, Q, R,    -   X5=Aad, Asu, D, E, N, Q,    -   X6=Aad, Asu, D, E, Har, K, N, Orn, Q, R,    -   X7=F, Hph, Hyp, NaI, P, Pip, W, Y, or deletion,    -   X8=A, α-Abu, β-A, G, S, T, V, Y, or deletion,    -   X9=amide, hydrazide, azide, carbamate, marker, spacer, linker,        C, GKK, SGKK (SEQ ID NO: 6) or deletion, or    -   b)    -   X1=amino group, amide, acetyl group, biotin group, marker,        spacer, linker, C, GKK, SGKK (SEQ ID NO: 6) or deletion,    -   X2=F, Hph, Hyp, NaI, P, Pip, W, Y,    -   X3=A, α-Abu, Dab, G, Hyl, K, Orn, R, S, V,    -   X4=Aad, Asu, D, E, Hyp, N, P, Pip, Q,    -   X5=Aad, Asu, D, E, Hyp, N, P, Pip, Q,    -   X6=A, α-Abu, G, Hyl, K, Orn, R, S, V    -   X7=F, Hph, Hyp, NaI, P, Pip, W, Y,    -   X8=γ-Abu, Ahx, β-A, G, or deletion,    -   X9=amide, hydrazide, azide, carbamate, marker, spacer, linker,        C, GKK, SGKK (SEQ ID NO: 6) or deletion, or    -   c)    -   X1=amino group, amide, acetyl group, biotin group, marker,        spacer, linker, C, GKK, SGKK (SEQ ID NO: 6) or deletion,    -   X2=A, α-Abu, Dab, G, Hyl, K, Orn, R, or deletion,    -   X3=A, C, F, Hph, M, NaI, S, W, Y,    -   X4=F, S, T, W, Y,    -   X5=F, S, T, W, Y,    -   X6=A, C, F, Hph, M, NaI, S, W, Y,    -   X7=A, α-Abu, Dab, G, Hyl, K, Orn, R,    -   X8=Abu, Ahx, β-A, G, or deletion,    -   X9=amide, hydrazide, azide, carbamate, marker, spacer, linker,        C, GKK, SGKK (SEQ ID NO: 6) or deletion, or    -   d)    -   X1=amino group, amide, acetyl group, biotin group, marker,        spacer, linker, C, GKK, SGKK (SEQ ID NO: 6) or deletion,    -   X2=Aad, Asu, D, E, F, Hph, N, NaI, Q, W, Y,    -   X3=A, C, G, Hcy, S, Sec,    -   X4=D, E, F, N, NaI, Q, W, Y,    -   X5=F, Hph, NaI, W, Y,    -   X6=D, E, F, N, NaI, Q, W, Y,    -   X7=A, C, G, Hcy, S, Sec,    -   X8=Aad, Asu, D, E, F, Hph, N, NaI, Q, W, Y,    -   X9=amide, hydrazide, azide, carbamate, marker, spacer, linker,        C, GKK, SGKK (SEQ ID NO: 6) or deletion        wherein Aad is α-aminoadipic acid; α-Abu is α-aminobutyric acid;        Ahx is ε-aminohexanoic acid; Asu is α-aminosuberic acid; β-A is        β-Alanine; Dab is α,γ-diaminobutyric acid; γ-Abu is        γ-aminobutyric acid; Har is homoarginine; Hcy is homocysteine;        Hph is homophenylalanine; Hyl is δ-hydroxylysine; Hyp is        hydroxyproline; NaI is β-(1- or 2-naphthyl)-alanine; Orn is        ornithine; Pip is pipecolic acid; Sec is selenocysteine and the        single letter code of amino acids represents the common L-amino        acids according IUPAC nomenclature as well as the corresponding        D-amino acids.

In a further embodiment of the invention the peptide according theinvention is characterized in that the linker and/or a spacer areselected from the group consisting of α-aminocarboxylic acids as well ashomo- and heterooligomers thereof, α,ω-aminocarboxylic acids andbranched homo- or heterooligomers thereof, other aliphatic and/oraromatic amino acids as well as linear and branched homo- orheterooligomers; amino-oligoalkoxyalkylamines; maleinimidocarb-oxylicacid derivatives; oligomers of alkylamines; 4-alkylphenyl derivatives;4-oligoalkoxyphenyl or 4-oligoalkoxyphenoxy derivatives;4-oligoalkyl-mercaptophenyl or 4-oligoalkylmercaptophenoxy derivatives;4-oligo-alkylaminophenyl or 4-oligoalkylaminophenoxy derivatives;(oligoalkylbenzyl)-phenyl or 4-(oligoalkylbenzyl)phenoxy derivatives, aswell as 4-(oligo-alkoxybenzyl)phenyl or 4-(oligoalkoxy-benzyl)phenoxyderivatives; trityl derivatives; benzyloxyaryl or benzyloxyalkylderivatives; xanthen-3-yloxyalkyl derivatives; (4-alkylphenyl)- orω-(4-alkylphenoxy)alkanoic acid derivatives; oligoalkylphenoxyalkyl oroligoalkoxyphenoxyalkyl derivatives; carbamate derivatives; amines;trialkylsilyl or dialkylalkoxysilyl derivatives; alkyl or arylderivatives and/or combinations thereof.

In yet another embodiment the peptide according to the invention ischaracterized in that it is selected from the group consisting of:

-   -   a) a peptide consisting of the amino acid sequence

X1-X2-X3-X4-X5-X6-X7-X8-X9

-   -   -   wherein X1 to X9 have the same meaning as mentioned            hereinabove;

    -   b) a peptide consisting of an amino acid sequence having        sufficient homology to be functionally analogous to an amino        acid sequence in accordance with a);

    -   c) a peptide according to an amino acid sequence a) or b) which        is modified by deletions, additions, substitutions,        translocations, inversions and/or insertions and functionally        analogous to an amino acid sequence in accordance with a) or b);

    -   d) a peptide according to amino acid sequence a), b) or c) which        is modified by branch or extension with the same or another        peptide according to amino acid sequence a), b) or c) to form a        homooligomeric or heterooligomeric peptide.

    -   e)

In a still further embodiment the peptide of the invention ischaracterized in that the amino acid sequence specified under b) has atleast 40% homology to any of the amino acid sequences specified undera). Moreover, the peptide of the invention is characterized in that theamino acid sequence specified under b) has at least 60%, preferably 70%,more preferably 80%, especially preferably 90% homology to any of theamino acid sequences specified under a).

In yet another embodiment of the invention the peptide of the inventionis characterized in that it consists of the amino acid sequence APEDET(SEQ ID NO: 1); WKEPAP (SEQ ID NO: 2); PPDERF (SEQ ID NO: 3); KMWTFG(SEQ ID NO: 4) or FGNFWCE (SEQ ID NO: 5).

According to the invention the peptide of the invention can be used as amedical active substance. The peptide according to the invention is ableto bind to antibodies of patients suffering from Morbus Alzheimer.

The peptide of the invention is furthermore characterized in that it maybe immobilized and/or fixed to magnetic, paramagnetic and/or nonmagnetic nanoparticles.

In still another embodiment of the invention, the peptide according tothe invention is characterized in that it is bound to a solid phase.

The peptide of the invention may be present in a linear and branched aswell as cyclic form. The peptide ring closure is e.g. effected throughdisulfide bridging when two cysteines are present, or through amidecyclization, which is optionally effected through side chains, throughthe C to the N termini or through a combination of the latter.

The peptide according to the invention may be further characterized inthat the immunoglobulins to which it binds are agAAB which interact withthe human β2-AR and α-AR.

The peptide according to anyone of the foregoing claims, characterizedin that it additionally comprises amino groups, amides, hydrazides,azides, carbamates, acetyl groups, biotin groups, markers, spacersand/or linkers.

Subject matter of the invention is also an isolated nucleic acidmolecule comprising:

-   -   a) a nucleic acid molecule comprising a nucleotide sequence        which encodes at least one peptide selected from the group        consisting of peptides according to the invention (above);    -   b) a nucleic acid molecule which is complementary to a        nucleotide sequence in accordance with a);    -   c) a nucleic acid molecule which undergoes hybridization with a        nucleotide sequence according to a) or b) under stringent        conditions;    -   d) a nucleic acid molecule comprising a nucleotide sequence        having sufficient homology to be functionally analogous to a        nucleotide sequence according to a), b) or c);    -   e) a nucleic acid molecule which, as a consequence of the        genetic code, is degenerated into a nucleotide sequence        according to a) through d); and    -   f) a nucleic acid molecule according to a nucleotide sequence        of a) through e) which is modified by deletions, additions,        substitutions, translocations, inversions and/or insertions and        functionally analogous to a nucleotide sequence according to a)        through e).

The nucleic acid molecule according to the invention having thenucleotide sequence specified under d) comprises at least 40%, inparticular at least 60%, preferably 70%, more preferably 80%, especiallypreferably 90% homology to any of the nucleotide sequences specifiedunder a) through c).

The nucleic acid molecule of the invention is a genomic DNA, a cDNAand/or an RNA.

Subject matter of the present invention is also a vector comprising anucleic acid molecule according to the invention.

Also a host cell is subject matter of the invention comprising thevector according to the invention.

Solid phases for affinity chromatography or solid-phase extraction aresubject matter of the invention too, comprising organic, inorganic,synthetic polymers or mixed polymers, preferably cross-linked agarose,cellulose, silica gel, polyamide and polyvinyl alcohols, which areoptionally chemically activated, with peptides according to theinvention, immobilized on the surface of the solid phase e.g. bycovalent bonding or by adsorption. In particular, the peptides can becovalently bound to the solid phase on position X1, X2, X3, X4, X5, X6,X7, X8 and/or X9. It may be advantageous that the peptides are distancedfrom the support surface by linkers or spacers.

Subject matter of the invention is also a device for removingimmunoglobulins from immunoglobulin-containing samples on solid phases,wherein the device contains the solid phase of the invention. Means forthe entry of immunoglobulin-containing samples can also be provided.

Another subject matter of the invention is a pharmaceutical compositioncomprising the nucleic acid molecule according to the invention, thevector according to the invention, the host cell according to theinvention, the peptide according to the invention, and/or the solidphase according to the invention, optionally together with apharmaceutically tolerable carrier substance.

Moreover, a kit comprising a nucleic acid molecule according to theinvention, a vector according to the invention, a host cell according tothe invention, a peptide according to the invention, a solid phaseaccording to the invention and/or a pharmaceutical composition accordingto the invention, optionally together with instructions for combiningthe contents of the kit and/or providing a formulation.

Subject matter of the invention is also an apparatus for chromatography,comprising peptides according to the invention. In particular, theapparatus is characterized in that the peptides are bound to the solidphase of the invention.

The invention is also concerned with the use of the nucleic acidmolecule of the invention, the vector according to the invention, thehost cell according to the invention, the peptide according to theinvention, the solid phase according to the invention, thepharmaceutical composition according to the invention, the kit accordingto the invention, the apparatus according to the invention in theprophylaxis, diagnosis, therapy of AD as well as in the production orscreening of a drug for the treatment of neurodegenerative diseases,such as AD.

The invention discloses also a method of treatment of Morbus Alzheimerby binding and/or removal of autoantibodies by means of peptidesaccording to the invention bound to a solid phase.

EXAMPLES, MATERIALS AND METHODS

Isolation and cultivation of neonatal heart cells were performed asdescribed previously (Wallukat, G. and Wollenberger, A. 1987. Effects ofthe serum gammaglobulin fraction of patients with allergic asthma anddilated cardiomyopathy on chronotropic β-adrenoceptor function incultured rat heart myocytes. Biomed. Biochim. Acta. 78:634-639)

Cell culture. Briefly, single cells were dissociated from the mincedventricles of Wistar rats (1-2 days old) with a 0.25% solution of crudetrypsin and were cultured as monolayers with a density of 800 cells/mm2in Halle SM 20-I medium equilibrated with humidified air. The mediumcontained 10% heat-inactivated FCS and 2 μmol/1 fluorodeoxyuridine(Serva, Heidelberg, Germany) the latter to prevent proliferation ofnonmuscle cells.

On the third or fourth days, the cells were incubated for 2 h in 2 mlfresh serum-containing medium. Seven to 10 selected cells orsynchronously contracting cell clusters per flask were counted for 15 s.The change of the pulsation rate were expressed as beats per minute.This procedure was repeated twice in different cultures to yield resultsrepresenting a total of up to 30 cells for each sample.

Immunoglobulin fractions, agonist and antagonist drugs, peptides etc.were added singly or cumulatively as indicated. The basal contractionrate of the spontaneously beating cardiomyocytes was 162±4 min.

Preparation of the immunoglobulin fraction. The immunoglobulin fractionwas isolated from 1- to 2-ml serum samples by ammonium sulfateprecipitation at a saturation of 40%. The precipitates were washed anddissolved in dialysis buffer (154 mmol/l NaCl, 10 mmol/l sodiumphosphate; pH 7.2). The procedure of precipitating, washing, anddissolving was repeated twice.

Finally, the immunoglobulins were taken up in 1 ml PBS (pH 7.2) anddialyzed at 4° C. for 30 hours against 11 of dialysis buffer. The bufferwas changed five times during dialysis. For detection of autoantibodies,the immunoglobulin fractions were added at a dilution of 1:20 or 1:40 tothe flasks.

After the dialysis, the IgG fractions feature a concentration of 10-15mg/ml, a maximum of 10 μg/ml of which are specific receptor antibodies.50 μl of this IgG solution are pre-incubated with the peptides with thefollowing concentration of peptides: 5 μl of a buffered solution of 100μg/ml per 50 μl IgG solution. This mixture is pre-incubated at roomtemperature for 30 minutes and subsequently filled into the cell culturevials, after the former nutrient solution has been removed by pipet. Theamount of the medium is 2 ml. The final concentration therefore is of0.5-0.75 mg/ml for the IgG and 0.5 μg for the peptides. If the molecularweight of the peptide (10 mer) is set with 1 KD and that of the IgG isset with 150 KD, there is an excess of agAAB.

For the neutralization experiments, synthetic peptides corresponding tothe sequence of the three extracellular loops of the human β2 AR orα1A-AR was added in excess (0.5 μg in 50 μl) to 50 μl of theimmunoglobulin fraction. The mixtures were shaken and incubated at roomtemperature for 1 h. The 100-μl samples were then added to neonatal ratheart muscle cells cultured in 2 ml medium to a final dilution of 1:40.The beating rate was counted for 15 s, about 60 min after the additionof the peptide/immunoglobulin mixture.

For identifying the autoantibody neutralizing epitopes syntheticoverlapping peptides corresponding to the sequence of the firstextracellular loop of the human β2-AR or second extracellular loop ofα1A-AR was added to the immunoglobulins. After 1 h incubation at roomtemperature the samples were used as described above.

ED50 calculation. For the estimation of the 50% effective dosage ofagAAB to stimulate neonatale rat cardiomyocytes the affinitychromatographic purified antibodies which bind to the epitopes in loop1of the human β2 adrenoceptor or loop2 of the human al adrenocepotor (subtype A) the antibodies were given into the tissue culture containingneonatal rat cardiomyocytes sequencially with increasing of antibodyconcentration until the maximum of the increase of the beating rate wasobserved. The ED50 was calculated by a computer program.

Patients. Sera of 14 patients with dementia of the Alzheimer type wererecruited from the Clinic of Psychiatry of the Hospital Luedenscheid.The controls are immunoglobulin fraction from the blood serum of healthydonors from the Max Delbrück Centre of Moleculare Medicine, Berlin.

For immunoglobulin preparation, the samples were centrifuged at 4,000 gfor 30 min and stored at −20° C. Reagents was purchased fromSigma-Aldrich Chemie (Deisenhofen, Germany). All other chemicals were ofanalytical grade.

Results

The figures show the following:

FIG. 1: Antibodies of patients (n=11-14) with Morbus Alzheimer stimulaterat cardiomyocytes via β2 adrenergic receptor and al adrenergicreceptor.

The β2 adrenergic antagonist ICI 118,551 blocks specifically butpartially the stimulating effects of the agonistic antibodies. A moreeffective inhibition of cellular activity of contraction is observed ifadditional the α adrenergic antagonist prazosin was given into the cellculture. 11 from 14 serum samples or immunoglobulins activate thecardiac myocytes.

FIG. 2: Antibodies from patients (n=6) with Morbus Alzheimer bind to thefirst extracellular loop of the β2 Adrenoceptor. After coincubation ofthe extracellular loop peptides 1, 2 or 3 with the immunoglobulins ofthe patients only the loop 1 neutralise the antibody mediated increaseof the cellular beating rate.

FIG. 3: Antibodies from patients (n=6) with Morbus Alzheimer bind to apeptide epitope embedded in the first extracellular loop of the β2-AR.After co-incubation of the immunoglobulins with overlapping epitopes (2amino acids) of the loop 1 peptides a neutralisation of antibodymediated increase of the beating rate was observed with the epitopeFGNFWCE (SEQ ID NO: 5).

FIG. 4: Antibodies of patients (n=6) with Morbus Alzheimer and directedto the β2 Adrenoceptor belong to the immunoglobulin G subclass 1. Afterco-incubation of the immunoglobulins with monoclonal antibodies specificfor the subclasses 1-4 only with the precipitate performed with themonoclonal antibody against IgG1 the antibody mediated activitydisappeared.

FIG. 5: Antibodies from patients (n=6) with Morbus Alzheimer bind to thesecond extracellular loop of the al Adrenoceptor. After co-incubation ofthe loops 1, 2 or 3 with the immunoglobulins of the patients only theloop 2 neutralise the antibody mediated increase of the cellular beatingrate.

FIG. 6: Antibodies from patients (n=5) with Morbus Alzheimer areneutralised by a peptide embedded in the second extracellular loop ofthe α1A Adrenoceptor. Overlapping peptides (one or two aminoacids) wereco-incubated with the immunoglobulins. The peptide with the amino acidsequence APEDET SEQ ID NO: 1) neutralises the cellular activity of theimmunoglobulins.

FIG. 7: Antibodies of patients (n=5) with Morbus Alzheimer and directedto the α1A Adrenoceptor belong to the immunoglobulin G subclass 1. Afterco-incubation of the immunoglobulins with monoclonal antibodies specificfor the subclasses 1-4 only with the precipitate performed with themonoclonal antibody against IgG1 the antibody mediated activitydisappeared.

1. A method of treating a disease caused by an increase of γ-secretaseactivity, an increased release of β-amyolid molecules and/or cellulardysfunction of cerebral blood vessel cells, glia cells or neurons,comprising the removal of immunoglobulins from patients suffering fromthe disease or being suspect to suffer from the disease.
 2. The methodof claim 1 wherein the disease is AD.
 3. The method of any of theforegoing claims wherein the removal is performed by immunoadsortion ofthe immunoglobulin.
 4. A peptide having an ED₅₀ of less than 500 nm, inparticular 10 nM to an antibody which recognizes an epitope on anextracellular α1 loop 2 or β2 loop1 of a human adrenoceptor (AR) whereinthe antibody's binding to the epitope results in an increase ofγ-secretase activity, an increased release of β-amyolid molecules and/orcellular dysfunction of cerebral blood vessel cells, glia cells orneurons, wherein the ED₅₀ value is measured by a bioassay.
 5. Thepeptide of claim 4 wherein the peptide recognizes the al extracellularloop1 epitopes of human α-AR subtypes A, B, or C or combinationsthereof, and the extracellular loop1 of a β2 AR, wherein thecombinations are A and B; A and C; B and C; A and B and C.
 6. Thepeptide of claim 4 or 5 consisting of an amino acid sequenceX1-X2-X3-X4-X5-X6-X7-X8-X9 wherein a) X1=amino group, amide, acetylgroup, biotin group, marker, spacer, linker, C, GKK, SGKK or deletion,X2=A, G, α-Abu, F, Hph, Hyp, NaI, P, Pip, S, V, W, Y, or deletion,X3=Hyp, P, Pip, S, T, Y, or deletion, X4=Aad, Asu, D, E, Har, K, N, Orn,Q, R, X5=Aad, Asu, D, E, N, Q, X6=Aad, Asu, D, E, Har, K, N, Orn, Q, R,X7=F, Hph, Hyp, NaI, P, Pip, W, Y, or deletion, X8=A, α-Abu, β-A, G, S,T, V, Y, or deletion, X9=amide, hydrazide, azide, carbamate, marker,spacer, linker, C, GKK, SGKK or deletion, or b) X1=amino group, amide,acetyl group, biotin group, marker, spacer, linker, C, GKK, SGKK ordeletion, X2=F, Hph, Hyp, NaI, P, Pip, W, Y, X3=A, α-Abu, Dab, G, Hyl,K, Orn, R, S, V, X4=Aad, Asu, D, E, Hyp, N, P, Pip, Q, X5=Aad, Asu, D,E, Hyp, N, P, Pip, Q, X6=A, α-Abu, G, Hyl, K, Orn, R, S, V X7=F, Hph,Hyp, NaI, P, Pip, W, Y, X8=γ-Abu, Ahx, β-A, G, or deletion, X9=amide,hydrazide, azide, carbamate, marker, spacer, linker, C, GKK, SGKK ordeletion, or c) X1=amino group, amide, acetyl group, biotin group,marker, spacer, linker, C, GKK, SGKK or deletion, X2=A, α-Abu, Dab, G,Hyl, K, Orn, R, or deletion, X3=A, C, F, Hph, M, NaI, S, W, Y, X4=F, S,T, W, Y, X5=F, S, T, W, Y, X6=A, C, F, Hph, M, NaI, S, W, Y, X7=A,α-Abu, Dab, G, Hyl, K, Orn, R, X8=Abu, Ahx, β-A, G, or deletion,X9=amide, hydrazide, azide, carbamate, marker, spacer, linker, C, GKK,SGKK or deletion, or d) X1=amino group, amide, acetyl group, biotingroup, marker, spacer, linker, C, GKK, SGKK or deletion, X2=Aad, Asu, D,E, F, Hph, N, NaI, Q, W, Y, X3=A, C, G, Hcy, S, Sec, X4=D, E, F, N, NaI,Q, W, Y, X5=F, Hph, NaI, W, Y, X6=D, E, F, N, NaI, Q, W, Y, X7=A, C, G,Hcy, S, Sec, X8=Aad, Asu, D, E, F, Hph, N, NaI, Q, W, Y, X9=amide,hydrazide, azide, carbamate, marker, spacer, linker, C, GKK, SGKK ordeletion wherein Aad is α-aminoadipic acid; α-Abu is α-aminobutyricacid; Ahx is ε-aminohexanoic acid; Asu is α-aminosuberic acid; β-A isβ-Alanine; Dab is α,γ-diaminobutyric acid; γ-Abu is γ-aminobutyric acid;Har is homoarginine; Hcy is homocysteine; Hph is homophenylalanine; Hylis δ-hydroxylysine; Hyp is hydroxyproline; NaI is β-(1- or2-naphthyl)-alanine; Orn is ornithine; Pip is pipecolic acid; Sec isselenocysteine and the single letter code of amino acids represents thecommon L-amino acids according IUPAC nomenclature as well as thecorresponding D-amino acids.
 7. The peptide according to anyone of theforegoing claims, characterized in that the linker and/or a spacer areselected from the group comprising: α-aminocarboxylic acids as well ashomo- and heterooligomers thereof, α,ω-aminocarboxylic acids andbranched—or heterooligomers thereof, other aliphatic and/or aromaticamino acids as well as linear and branched homo- or heterooligomers;amino-oligoalkoxyalkylamines; maleinimidocarboxylic acid derivatives;oligomers of alkylamines; 4-alkylphenyl derivatives; 4-oligoalkoxyphenylor 4-oligoalkoxyphenoxy derivatives; 4-oligoalkylmercaptophenyl or4-oligoalkylmercaptophenoxy derivatives; 4-oligo-alkylaminophenyl or4-oligoalkylaminophenoxy derivatives; (oligoalkylbenzyl)phenyl or4-(oligoalkylbenzyl)phenoxy derivatives, as well as4-(oligo-alkoxybenzyl)phenyl or 4-(oligoalkoxy-benzyl)phenoxyderivatives; trityl derivatives; benzyloxyaryl or benzyloxyalkylderivatives; xanthen-3-yloxyalkyl derivatives; (4-alkylphenyl)- orco-(4-alkylphenoxy)alkanoic acid derivatives; oligoalkylphenoxyalkyl oroligoalkoxyphenoxyalkyl derivatives; carbamate derivatives; amines;trialkylsilyl or dialkylalkoxysilyl derivatives; alkyl or arylderivatives and/or combinations thereof.
 8. The peptide according toanyone of the foregoing claims, characterized in that it is selectedfrom the group consisting of: a) a peptide consisting of the amino acidsequenceX1-X2-X3-X4-X5-X6-X7-X8-X9 according to claim 7; b) a peptide consistingof an amino acid sequence having sufficient homology to be functionallyanalogous to an amino acid sequence in accordance with a); c) a peptideaccording to an amino acid sequence a) or b) which is modified bydeletions, additions, substitutions, translocations, inversions and/orinsertions and functionally analogous to an amino acid sequence inaccordance with a) or b); d) a peptide according to amino acid sequencea), b) or c) which is modified by branch or extension with the same oranother peptide according to amino acid sequence a), b) or c) to form ahomooligomeric or heterooligomeric peptide.
 9. The peptide according toanyone of the foregoing claims, characterized in that the amino acidsequence specified under b) has at least 40% homology to any of theamino acid sequences specified under a).
 10. The peptide according toanyone of the foregoing claims, characterized in that the amino acidsequence specified under b) has at least 60%, preferably 70%, morepreferably 80%, especially preferably 90% homology to any of the aminoacid sequences specified under a).
 11. The peptide according to anyoneof the foregoing claims, characterized in that it consists of the aminoacid sequence APEDET; WKEPAP; PPDERF; KMWTFG or FGNFWCE.
 12. The peptideaccording to anyone of the foregoing claims for use as a medical activesubstance.
 13. The peptide according to anyone of the foregoing claims,characterized in that the peptide binds to antibodies of patientssuffering from AD.
 14. The peptide according to anyone of the foregoingclaims, characterized in that the peptide is immobilized and/or fixed tomagnetic, paramagnetic and/or non magnetic nanoparticles.
 15. Thepeptide according to anyone of the foregoing claims, characterized inthat the peptide is bound to a solid phase.
 16. The peptide according toanyone of the foregoing claims in a linear and branched as well ascyclic form, wherein the peptide ring closure is effected throughdisulfide bridging when two cysteines are present, or through amidecyclization, which is optionally effected through side chains, throughthe C to the N termini or through a combination of these last twopossibilities.
 17. The peptide according to anyone of the foregoingclaims, characterized in that the immunoglobulins are agonisticautoantibodies which interact with the α-adrenoreceptor receptor. 18.The peptide according to anyone of the foregoing claims, characterizedin that it additionally comprises amino groups, amides, hydrazides,azides, carbamates, acetyl groups, biotin groups, markers, spacersand/or linkers.
 19. An isolated nucleic acid molecule selected from thegroup comprising: a) a nucleic acid molecule comprising a nucleotidesequence which encodes at least one peptide selected from the groupconsisting of peptides according to claim 4; b) a nucleic acid moleculewhich is complementary to a nucleotide sequence in accordance with a);c) a nucleic acid molecule which undergoes hybridization with anucleotide sequence according to a) or b) under stringent conditions; d)a nucleic acid molecule comprising a nucleotide sequence havingsufficient homology to be functionally analogous to a nucleotidesequence according to a), b) or c); e) a nucleic acid molecule which, asa consequence of the genetic code, is degenerated into a nucleotidesequence according to a) through d); and f) a nucleic acid moleculeaccording to a nucleotide sequence of a) through e) which is modified bydeletions, additions, substitutions, translocations, inversions and/orinsertions and functionally analogous to a nucleotide sequence accordingto a) through e).
 20. The nucleic acid molecule according to claim 19,characterized in that the nucleotide sequence specified under d) has atleast 40% homology to any of the nucleotide sequences specified under a)through c).
 21. The nucleic acid molecule according to claim 19,characterized in that the nucleotide sequence specified under d) has atleast 60%, preferably 70%, more preferably 80%, especially preferably90% homology to any of the nucleotide sequences specified under a)through c).
 22. The nucleic acid molecule according to any of claims 19to 21, characterized in that it is a genomic DNA, a cDNA and/or an RNA.23. A vector comprising a nucleic acid molecule according to any ofclaims 19 to
 22. 24. A host cell comprising the vector according toclaim
 23. 25. A peptide, said peptide being encoded by a nucleic acidmolecule according to any of claims 19 to
 22. 26. Solid phases foraffinity chromatography or solid-phase extraction consisting of organic,inorganic, synthetic polymers or of mixed polymers, preferablycross-linked agarose, cellulose, silica gel, polyamide and polyvinylalcohols, which are optionally chemically activated, with peptidesaccording to at least one of claims 4 to 18, 25, immobilized on thesurface of the solid phase.
 27. The solid phases according to claim 26,wherein the peptides are bound to the solid support phase covalently orby adsorption.
 28. The solid phases according to claim 26 and/or 27,wherein the peptides are covalently bound to the solid phase on positionX1, X2, X3, X4, X5, X6, X7, X8 and/or X9.
 29. The solid phases accordingto any of claims 26 to 28, wherein the peptides are distanced from thesupport surface by linkers/spacers.
 30. A device for removingimmunoglobulins from immunoglobulin-containing samples on solid phases,wherein the device contains a solid phase according to any of claims 26to 29, and means for the entry of immunoglobulin-containing samples areprovided.
 31. A pharmaceutical composition comprising a nucleic acidmolecule according to any of claims 19 to 22, a vector according toclaim 23, a host cell according to claim 24, a peptide according to anyof claims 4 to 17, 25, and/or a solid phase according to claims 27 to29, optionally together with a pharmaceutically tolerable carrier.
 32. Akit comprising a nucleic acid molecule according to any of claims 19 to22, a vector according to claim 23, a host cell according to claim 24, apeptide according to any of claims 4 to 18, 25, a solid phase accordingto claims 26 to 29 and/or a pharmaceutical composition according toclaim 31, optionally together with instructions for combining thecontents of the kit and/or providing a formulation.
 33. An apparatus forchromatography, comprising peptides according to any of claims 4 to 18,25.
 34. The apparatus according to claim 33, characterized in that thepeptides are bound to a solid phase according to claims 25 to
 29. 35.Use of a nucleic acid molecule according to any of claims 19 to 22, avector according to claim 23, a host cell according to claim 24, apeptide according to any of claims 4 to 18, 25, a solid phase accordingto claims 26 to 29, a pharmaceutical composition according to claim 31,a kit according to claim 32, an apparatus according to claim 33 or 34 inthe prophylaxis, diagnosis, therapy, follow-up and/or aftercare ofMorbus Alzheimer.
 36. Use of a nucleic acid molecule according to any ofclaims 19 to 22, a vector according to claim 23, a host cell accordingto claim 24, a peptide according to any of claims 4 to 18, 25, a solidphase according to claims 26 to 29, a pharmaceutical compositionaccording to claim 31, a kit according to claim 32, an apparatusaccording to claim 33 or 34 in the production or screening of a drug forthe treatment of neurodegenerative diseases, such as AD.
 37. Use of animmunoadsorption device for manufacturing a device for the treatment ofa disease caused by an increase of γ-secretase activity, an increasedrelease of β-amyolid molecules and/or cellular dysfunction of cerebralblood vessel cells, glia cells or neurons by removal of immunoglobulinsfrom patients.
 38. A method for the treatment of Morbus Alzheimer bybinding and/or removal of autoantibodies by means of peptides accordingto any of claims 4 to 18, 25 bound to a solid phase.